Project 3 Project Summary/Abstract Disruption of circadian rhythms in activity, sleep-wake cycle, and other physiologic parameters is a consequence of aging, and occurs prominently in Alzheimer's Disease (AD). While circadian dysfunction is a major cause of morbidity in AD, it is unknown if it contributes to disease pathogenesis. Systemic circadian rhythms in mice and humans are regulated by the suprachiasmatic nucleus (SCN) of the hypothalamus, which synchronizes peripheral oscillations of core clock genes in all organs with the light-dark cycle. Our preliminary data shows that genetic deletion of core circadian clock genes, which mediate circadian transcriptional oscillations, can cause neuronal oxidative stress and neurodegeneration, suggesting that disruption of whole- animal SCN-driven circadian rhythms might have deleterious effects in AD through clock gene dysregulation. Human pathologic studies suggest that the SCN is a site of neuropathology in AD, though the impact of SCN dysfunction on AD pathogenesis is unknown. The objective of this Project is to test the hypothesis that impaired SCN-mediated circadian rhythms will increase amyloid-beta (A) pathology, synaptic injury, and oxidative stress in mouse models of AD and in human AD patients. We will examine how lesioning of the SCN, which abrogates systemic circadian rhythms in mice, alters sleep-wake parameters and circadian patterns of cortical and hippocampal gene expression in 2 mouse models of A accumulation. We will determine if SCN lesioning accelerates A plaque deposition in these mouse models, and examine if loss of SCN-mediated rhythms affects A-induced synaptic injury, neuroinflammation, and oxidative damage. Finally, we will examine correlations between circadian patterns in activity (actigraphy) and cerebrospinal fluid markers of oxidative stress and AD pathology in older adults and individuals with preclinical AD. These studies are designed to reveal dysfunction of SCN-mediated circadian rhythms as a contributing factor in AD pathogenesis, suggesting that therapies targeting the circadian system might prevent or delay AD.